Abstract Stroke commonly occurs in children with sickle cell anemia (SCA) due to development of sickle cerebral vasculopathy (SCV) injury. SCV also can cause neurocognitive impairment. Identifiable stroke risk is associated with abnormal cerebral abnormal arterial blood flow detected by transcranial Doppler ultrasound (TCD). Most children with SCA live in Africa. Our hypotheses are that: 1) Higher burden of anemia, inflammation and malnutrition predispose African children with SCA to greater burden of SCV than in the West; 2) in Uganda, HU therapy will prevent, stabilize or improve SCV and its effects. We propose to: in Aim 1 to perform an open label, single arm clinical trial to test the three-year impact of hydroxyurea treatment for a cohort of children with SCA ages 2-9 years in Uganda on each of three clinically important outcomes: abnormal TCD, neurocognitive impairment, and first stroke. Following baseline assessments, all subjects will begin hydroxyurea therapy at about 20mg/kg daily. Changes in the frequency and severity of each outcome will be compared with age-adjusted baseline test results by repeating these three tests at 18 and 36 months; in Aim 2 to evaluate the impact of HU on structural vascular injury using MRI and MRA in a randomly selected 33% subset of this cohort at baseline and at 36 months; in Aim 3 we will assess changes to biomarkers of anemia, C-reactive protein and malnutrition status during hydroxyurea therapy, over time, compared with baseline levels, and determine their relationship to the development of brain injury and the other findings. Our proposed intervention with hydroxyurea is the only Africa-based trial to broadly prevent or ameliorate manifestations of SCV.